Focal Defects in Single-Celled Tubes Mutant for Cerebral Cavernous Malformation 3, GCKIII, or NSF2

• DOI: 10.1016/j.devcel.2013.05.002
• Publication Date: 2013-06-10T15:33:51Z
• Authors: Yanjun Song; Melissa Eng; Amin S. Ghabrial
• Keywords: 0301 basic medicine; Cellular signal transduction; Genotype; Molecular Sequence Data; 610; Protein Serine-Threonine Kinases; Germinal Center Kinases; 03 medical and health sciences; Proto-Oncogene Proteins; 616; Genetics; Animals; Drosophila Proteins; Amino Acid Sequence; N-Ethylmaleimide-Sensitive Proteins; Alleles; Sequence Homology, Amino Acid; Genetic Complementation Test; Membrane Proteins; Trachea; Drosophila melanogaster; Phenotype; FOS: Biological sciences; Mutation; Drosophila; Apoptosis Regulatory Proteins; Cytology; Developmental Biology

Tubes of differing cellular architecture connect into networks. In the Drosophila tracheal system, two tube types connect within single cells (terminal cells); however, the genes that mediate this interconnection are unknown. Here we characterize two genes that are essential for this process: lotus, required for maintaining a connection between the tubes, and wheezy, required to prevent local tube dilation. We find that lotus encodes N-ethylmaleimide sensitive factor 2 (NSF2), whereas wheezy encodes Germinal center kinase III (GCKIII). GCKIIIs are effectors of Cerebral cavernous malformation 3 (CCM3), a protein mutated in vascular disease. Depletion of Ccm3 by RNA interference phenocopies wheezy; thus, CCM3 and GCKIII, which prevent capillary dilation in humans, prevent tube dilation in Drosophila trachea. Ectopic junctional and apical proteins are present in wheezy terminal cells, and we show that tube dilation is suppressed by reduction of NSF2, of the apical determinant Crumbs, or of septate junction protein Varicose.